Body cavity foams

ABSTRACT

The invention relates to an alcohol-free cosmetic or therapeutic foam carrier comprising water, a hydrophobic organic carrier, a foam adjuvant agent, a surface-active agent and a gelling agent. The cosmetic or therapeutic foam carrier does not contain aliphatic alcohols, making it non-irritating and non-drying. The alcohol-free foam carrier is suitable for inclusion of both water-soluble and oil soluble therapeutic and cosmetic agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of co-pendingInternational Patent Application No. IB03/005527, designating the UnitedStates and filed on Oct. 24, 2003, which claims the benefit of priorityunder 35 U.S.C. §119(e) to U.S. patent application Ser. No. 60/492,546,filed on Nov. 29, 2002, both entitled “Cosmetic and PharmaceuticalFoam,” and which claims the benefit of priority under 35 USC§119(a) toIsraeli Patent Application. No. 152486, filed Oct. 25, 2002, all ofwhich are hereby incorporated in their entirety by reference.

This application is a continuation-in-part application of co-pendingU.S. patent application Ser. No. 10/911,367, filed on Aug. 4, 2004,which claims the benefit of priority under 35 U.S.C. §119(e) to U.S.patent application Ser. No. 60/492,385, filed on Aug. 4, 2003, bothentitled “Foam Carrier Containing Amphiphilic Copolymer Gelling Agent”and both hereby incorporated in their entirety by reference.

This application claims the benefit of priority under 35 U.S.C. §119(e)to U.S. patent application Ser. No. 60/566,513, filed on Apr. 28, 2004,entitled “Intravaginal Foam,” which is incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to an alcohol-free, foam carrier for delivery ofan active agent to a mucosal body cavity. More specifically, theinvention relates to foam carriers suitable for inclusion of poorlysoluble, water soluble and oil soluble therapeutic agents for deliveryand sustained release to the vaginal cavity.

BACKGROUND OF THE INVENTION

The vaginal cavity, including the vagina and cervix, provides a uniquesite for delivery of therapeutic agents, both for systemic and localaction.

There are multiple anatomical structures which comprise the internal andexternal female genital tract including the clitoris, labia minora andcorpus spongiosum (vestibular) erectile tissue, vagina, peri-urethralglans, urethra, Halban's fascia, anterior formix erogenous zone,pubococcygeus muscle and cervix.

The vagina consists of a tube of autonomically-innervated smooth muscle(longitudinal outer, inner circular layer) lined by stratified squamousepithelium and a sub-dermal layer rich in capillaries. The vaginal wallconsists of an inner glandular mucous type stratified squamous cellepithelium supported by a thick lamina propia. This epithelium undergoeshormone-related cyclical changes including slight keratinization of thesuperficial cells during the menstrual cycle. Deep in the epitheliumlies the smooth muscles of the muscularis. There is a deeper surroundingfibrous layer above the muscularis which provides structural support tothe vagina and is rich is collagen and elastin to allow for expansion ofthe. Three sets of skeletal muscles surround the vagina including theischiocavernosum, bulbocavernosus, transverse perinei and levator aniand pubococcygeus muscles.

Women are vulnerable to diseases of the genital tract as the lining ofthe vagina is a permeable mucous membrane. Intercourse, lack oflubrication during intercourse, changes in the cervix during themenstrual cycle, and asymptomatic infections facilitate the transmissionof infection to women. Prepubertal girls and adolescents areparticularly vulnerable because their vaginal and cervical tissues maybe less mature and are more readily penetrated by organisms (e.g.,chlamydia and gonococcus). Postmenopausal women are more likely thanyounger women to get small abrasions in the vagina during sexualactivity as a result of thinning of the tissue and dryness. Women whoalready have an infection (particularly one that causes genital lesions)are more likely to acquire or transmit another STD, including HIV. Otherbiological risks include the use of vaginal douches, which increase therisk of pelvic inflammatory disease (PID), and the influence of hormonalcontraceptives on acquiring or transmitting an STD (e.g., increased riskof chlamydial infection with use of oral contraceptives).

In particular, the cervix is prone to several diseases, such ascervicitis (an inflammation of the uterine cervix, usually caused byinfection), cancer, inflammation, erosion, intraepithelial neoplasia(CIN), polyps, dysplasia, human papillomavirus (HPV) infections causingsome tumors, condylomas or warts and abnormal pregnancy.

Several factors must be taken into consideration when developingtherapeutic delivery systems for the female genital system. Thesefactors include the vaginal anatomy, the mucosal surface, the presenceand composition of vaginal fluids and secretions, cervical fluids(mucus), cyclic changes and endogenous microflora. Drug stability toenzyme activity, which is quite high in vaginal environment, and isagain a function of menstrual cycle and lifecycle, should also be takeninto account. Topical drug delivery through the cervix, as needed totreat disorders of the cervix and uterus also presents a challenge.

Vaginal topical formulation should be compatible with daily activities,be easy to administer and provide accurate dosing. Several types offormulations are known for delivery to the vaginal cavity. Whilesemi-solid formulations, such as creams, lotions, gels and ointments arecommonly used, they are often reported to be messy, require frequentapplication and can be difficult to remove after use. Furthermore,application of topical gels and creams require several steps ofoperation. Solid formulations such as tablets, suppositories andpessaries also require frequent application, show a poor retention invagina, and exhibit insufficient spreadability.

Rectal drug administration can be directed to both local and systemicdrug delivery. It has been effectively used to treat local diseases ofthe anorectal area as well as an alternative to oral administration inthe systemic administration of drugs. Solid suppositories are the mostcommon dosage form used for rectal drug administration and represent themajority of rectal dosage forms; however, creams ointments and foams arealso being used.

Current formulations for rectal administration still have significantdisadvantages. They are difficult to insert through the anal orifice;they are difficult to spread throughout the target cavity; and ifspreadable, they tend to leak, causing major discomfort to the patient.Such negative attributes lead to their very limited use.

Thus, new forms are desirable in order to achieve better control andease of application, while maintaining the beneficial properties of suchproducts. A product for intravaginal and anorectal application wouldideally exhibit the following properties: (1) easy insertion, thusleading to high patient compliance; (2) accurate dosing, to ensureeffective treatment; (3) expandability, for increased coverage of thetarget cavity surface and cervix; and (4) drip free formulation withgood adhesive properties, for prolonged drug residence. The duration ofthe drug inside the vagina or rectum is also important for ensuringextended activity.

Use of emulsions in foam compositions is known. Emulsion systems providea two-phase system including water in one phase and oily components inthe second phase. Emulsifiers for reducing surface tension and forimproving foam stability are included in the foam composition. Foamsand, in particular, foam emulsions are complicated systems which do notform under all circumstances. Slight shifts in foam emulsioncomposition, such as by the addition of active ingredients, maydestabilize the foam. In the case of oil-containing foams, highsurfactant concentrations are required to attain foams of low densityand acceptable texture.

Typical vaginal foam products are aqueous formulations and do notinclude significant levels of an oil-based solvent. For example. anonoxynol-9-containing foam marketed under the trademane Delfen® foam(Advanced care, 12.5% nonoxynol-9), Emko® foam (Schering-PloughHealthcare, 12% nonoxynol-9) does not contain any oily solvent and hasan ingredient list reciting “nonoxynol-9 12.5%, benzoic acid, cetylalcohol, glacial acetic acid, methylparaben, perfume, phosphoric acid,polyvinyl alcohol, propellant a-31, propylene glycol, purified water,sodium carboxymethylcellulose, sorbic acid, stearamidoethyldiethylamine, stearic acid”.

PCT Publication No. WO 03/053292 discloses drug delivery compositions,which are suitable for vaginal administration for the treatment ofdiseases and disorders in the urogenital tract. The compositions may bein the form of a tablet, liquid suspension or dispersion; dried powder;topical ointment; cream; foam; suppository; or aerosol. The drugdelivery compositions are administered directly to the vagina and do notrequire the use of a pressurized canister or other foaming device. Thereference does not disclose use of hydrophobic or oily solvents.

U.S. Pat. No. 5,759,520 discloses an aqueous foamable composition havinga delayed foaming action on expulsion from a pressurized container. Thecomposition includes (a) a major amount by weight of water; (b) 0.5 to7.0 weight percent of a foaming agent in the form of a water-immiscibleliquefied gas; (c) at least one foam-stabilizing and emulsifyingsurfactant; and (d) a water-soluble polymer. A foaming agent such aspropellant gas forms a foam upon discharge from the container. Water isused as the foam vehicle and hydrophobic organic carriers such as oil oremollients are not disclosed.

PCT Publication No. WO 02/00820 discloses a propellant-free foamableaqueous composition for use as vaginal or hemorrhoidal wipe. The aqueousstable foam includes water, at least one surfactant and at least onefoam-stabilizing agent. Such compounds are storage stable and readilydispensed by a propellantless mechanical pump.

U.S. Pat. No. 5,679,324 pertains to an aerosol foamable fragrancecomposition, translucent in its pre-dispensed state, which forms afast-breaking foam. The composition contains a surfactant selected fromthe group consisting of ethoxylated lanolin oil derivatives,propoxylated lanolin oil derivatives, and mixtures thereof, apropellant, a fragrance, a thickener, and a cosmetic vehicle (preferablywater) wherein the ratio of the surfactant to propellant is from about1:1 to about 1:10. Emollients may be included, however, beingtranslucent, the composition cannot comprise significant oilconcentrations (which would make it opaque). Apparently the foam breaksspontaneously upon discharging from an aerosol container (with no needof any rubbing or sheer force application), thus making it impracticalfor intravaginal application.

Additionally, U.S. Pat. Nos. 5,536,743 and 5,840,744 relate to anon-flowing composition and method for intravaginal treatment ofbacterial vaginosis. The composition contains metronidazole with abuffer system providing an acidic buffered pH value in the range of 3.75to about 4.25. Certain of the compositions disclosed are based onmineral oil or petrolatum. The foam compositions disclosed include up to3% mineral oil as the hydrophobic component of the emulsion.

U.S. Pat. No. 6,544,530 provides a stable oil-in-glycerin compositioncomprising a continuous glycerin phase, at least one vegetable oil, atleast one biodegradable emulsifier and at least one bioactive essentialoil component for topical, external use on skin and mucosal. Theessential oil is a volatile mixture of esters, aldehydes, alcohols,ketones, and terpenes that possess bioactivity such as topicalanti-fungal activity, topical anti-bacterial activity, topicalanti-parasitic activity, and topical anti-viral activity.

U.S. Pat. No. 5,993,846 discloses a method for making an oil-in-wateremulsion having mucoadhesive properties which includes forming a mixtureof a mucoadhesive macromolecule and an aqueous phase; emulsifying themixture with a hydrophobic phase and a surfactant to form anoil-in-water emulsion comprising a plurality of submicron particleshaving a hydrophobic core surrounded by the surfactant and themucoadhesive macromolecule; and providing the emulsion with a final pHof between 3 and 8.

U.S. Pat. No. 6,423,323 describes an aqueous foam emulsion. Thecomposition includes a hydrophobic phase including fatty acids,emulsifiers and co-emulsifiers, and an aqueous phase containinghydrophilic moisturizers and emulsifiers. An optional ingredient is oneor more refatting substances.

U.S. Pat. No. 6,730,288 teaches a pharmaceutical foam compositionincluding (a) an active ingredient; (b) an occlusive agent; (c) anaqueous solvent; and (d) an organic cosolvent; wherein the activeingredient is insoluble in water and insoluble in both water and theocclusive agent; and wherein there is enough occlusive agent to form anocclusive layer on the skin.

SUMMARY OF THE INVENTION

In some aspects, the present invention provides an easy to use vaginaldelivery system that will be simple to operate with minimal preparation,will be very tolerable without having a feeling of foreign matter, willprovide accurate dose administration, will evenly spread throughout thevaginal cavity surface, will effectively reach the cervix, will not leakand will retain intravaginally an active agent for a significant periodof time. In other aspects, the present invention provides a lubricatingvaginal drug vehicle for moisture replenishing or moisturizing vaginalvehicles. In other aspects, the invention provides an improved deliverysystem for active agents to other body cavities, such as the rectum,penile urethra, nasal cavity and ear cavity and to mucosal surfaces.

The present invention relates to foam compositions for intra-vaginal andbody cavity application of a wide range of active ingredients. Thecompositions contain at least one active agent in a biocompatiblealcohol-free foamable carrier, including oleaginous foams, oil-in-waterfoams, water-in-oil foams, liposome-based foams and nanoparticle-basedfoams. These compositions provide long lasting, drip-free, expandableformulations for drug delivery into body cavities.

According to one aspect of the present invention, an alcohol-freefoamable therapeutic composition for application to a body cavity or amucosal surface includes:

-   -   at least one organic carrier selected from a hydrophobic organic        carrier, a polar solvent, an emollient and mixtures thereof        hydrophobic organic carrier and mixtures thereof, at a        concentration of about 2% to about 75% by weight;    -   about 0.2% to about 5% by weight at least one surface-active        agent;    -   about 0.01% to about 5% by weight at least one polymeric agent,        selected from a bioadhesive agent, a gelling agent, a film        forming agent and a phase change agent; at least one active        agent at a therapeutically effective concentration; and    -   a liquefied or compressed gas propellant at a concentration of        about 3% to about 25% by weight of the total composition, which        upon release from an aerosol container provides an expanded foam        suitable for topical administration.

According to one embodiment, the composition further includes a foamadjuvant at a concentration less than about 5% by weight. Water andoptional ingredients added to complete the total mass to 100%. Thecontent of the foam compositions is presented herein as concentration(percent by weight, % w/w).

According to one or more embodiments of the present invention, thesolvent level varies and can be at a level of about 2 to about 5, about5% to about 20% by weight, or at a concentration of about 20% to about75% by weight.

In another aspect of the present invention, an alcohol free oleaginoustherapeutic foam composition for administration to a body cavity ormucosal surface includes:

-   -   at least one organic carrier selected from a hydrophobic organic        carrier, an emollient, a polar solvent, and mixtures thereof, at        a concentration of about 70% to about 99% by weight;    -   at least one surface-active agent at a concentration of about        0.2 to about 15%;    -   at least one polymeric agent, selected from a bioadhesive agent,        a gelling agent, a film forming agent and a phase change agent        at a concentration of about 0.1% to about 5% by weight;    -   at least one active agent at a therapeutically effective        concentration; and    -   a liquefied or compressed gas propellant at a concentration of        about 3% to about 25% by weight of the total composition, which        upon release from an aerosol container provides an expanded foam        suitable for topical administration.

Water and optional ingredients are added to complete the total mass to100%. As used herein “oleaginous foam composition” means a stable foamcomposition, or a composition capable of forming a stable foamcomposition that contains a high level of oil or emollient as thehydrophobic organic carrier. The hydrophobic organic carrier is includedin the oleaginous foam composition at levels at or above 70%, and up toabout 99% by weight.

According to one embodiment, at least one of the composition components,selected from the group consisting of organic carrier, surface activeagent, foam adjuvant or polymeric agent can also function as an activeagent.

In another aspect of the present invention, a method of making afoamable composition includes selecting at least one active agent;selecting a solvent that solubilizes the active agent substantiallybetter than a hydrocarbon solvent such as mineral oil or petrolatum, forexample, 5 fold better than mineral oil or petrolatum, or even 10-foldbetter than mineral oil or petrolatum; and adjusting the type andconcentration of surfactant and gelling agent, to provide a foamablecomposition.

According to another aspect of the present invention, a method oftreating a syndrome, disease or disorder of a body cavity or mucosalsurface includes administering an alcohol-free foamable therapeuticcomposition. The foamable composition can be an oleaginous foam, anoil-in-water foam, a water-in-oil foam, a liposome based foam and ananoparticle based foam.

In one or more embodiments of the present invention, the syndrome,disorder or disease of the body cavity is a syndrome, disorder ordisease of the vaginal cavity. In one or more embodiments, the disorderis a microbial disorder including bacterial vaginosis, candidiasis,candidal vaginitis and trichomonas vaginitis. In another embodiment themicrobial disorder is a sexually transmitted disease (STD) such aschlamydia, herpes simplex, human immunodeficiency virus (HIV). Inanother embodiment the syndrome, disorder or disease of the vaginalcavity is related to hormonal or post-menopausal vaginal dryness. In yetanother embodiment the syndrome, disorder or disease is related to thecervix and includes malignant and benign tumors, dysplasias, humanpapillomavirus (HPV) or to the vulva and includes lichen sclerosus,vulvodynia and other pathologies.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a foamable therapeutic compositionsuseful for delivery of an active agent to a mucosal body cavity. Thecomposition is dispensed as a foam providing a stable product that ispleasant and easy to use for high patient compliance.

The foamable therapeutic composition of the present invention issuitable for facile administration into the rectum, bladder, the cavitybetween the uterus and the fallopian tubes, the ovaries and other bodyareas, which may accept topically-applied products.

In one or more embodiments of the present invention, a foamablecomposition includes water in one phase and at least one solventselected from a hydrophobic organic carrier, a polar solvent, anemollient and mixtures thereof in the second phase. The compositions maybe water-in-oil or oil-in-water emulsions.

Despite the commonly accepted understanding that hydrophobic organiccarriers, polar solvents and emollients are difficult to formulate intoa foam-producing product and that addition of such solvents interfereswith the foam forming ability of a surfactant, the present invention hassurprisingly identified a series of foam compositions, which, uponadmixing with a liquefied gas propellant in an aerosol container,produce a stable foam composition that is suitable for topical andmucosal administration to body cavities, such as the vagina, rectum,penile, urethra, nasal cavity and ear cavity. Upon discharge from anaerosol container, the composition forms an expanded foam, which doesnot break down immediately upon discharge, and remains in the bodycavity for an extended time.

Such compositions, when placed in an aerosol container and combined witha liquefied gas propellant, create an emulsion, which, upon release fromthe aerosol container, provides a therapeutically beneficial foamproduct.

According to one or more embodiments of the present invention, thetherapeutic foam composition for administration to a body cavity ormucosal surface includes at least one solvent selected from ahydrophobic organic carrier, a polar solvent, an emollient and mixturesthereof, at a level of about 2% to about 5%, or about 5% to about 10%;or about 10% to about 20%; or about 20% to about 75%; or about 70% toabout 99% by weight. The composition also contains about 0.2% to about5% by weight of a surface-active agent; about 0.01% to about 5% byweight of a polymeric additive selected from a bioadhesive agent, agelling agent, a film forming agent and a phase change agent; at leastone active agent at a therapeutically effective concentration; and aliquefied gas propellant at a concentration of about 3% to about 25% byweight of the total composition, which upon release from an aerosolcontainer provides an expanded foam suitable for topical administration.

According to one embodiment, the composition further comprises a foamadjuvant at a concentration less than about 5%.

Water (to make an emulsion) and optional ingredients are added tocomplete the total mass to 100%. Upon release from an aerosol container,the foamable composition forms an expanded foam suitable for topicaladministration.

In one or more embodiments, the foam composition is formulated as anemulsion and can be an oil-in-water emulsion or a water-in-oil emulsion.The choice of the type of emulsion (oil-in-water or water-in-oil) ismade in light of the nature of the active agent, so that it is suitablefor inclusion of either or both water-soluble and oil-soluble activeagents. The choice of the type of emulsion is also influenced by thetype of interaction which is desirable between the composition, theactive agent and the target tissue.

In one or more embodiments, the emulsion is a micro-emulsion.Microemulsions are dispersions of either oil-in-water or water-in-oil,which are typically clear, as the droplet diameter is approximately 100nanometers (nm) or less.

In one or more embodiments, the foam composition of the presentinvention comprises liposomes.

In one or more embodiments, the foam composition of the presentinvention comprises nanoparticles, and, for example, the diameter isabout 200 nm to about 400 nm. Nanoparticles are typically introduced asan active agent.

The foam composition may include a propellant substance in an amount ofabout 3% to about 25% by weight, housed in an aerosol container.

When released, the composition produces a foam, suitable for facileadministration into body orifices and mucosal cavities, including, butnot limited to the the vagina, the rectum and penile cavities, theurinary tract, bladder, the cavity between the uterus and the fallopiantubes, the ovaries and other body areas, which may accepttopically-applied products.

It has been surprisingly discovered that the propellant helps provide astable emulsion. The propellant makes up part of the “oil phase”component of the emulsion, providing a product with long shelf-life.Thus, admixing the liquid and solid foam components with a short chainhydrocarbon propellant, results in a stable emulsion, that does notundergo phase separation after stress test, including either exposure toat least two freeze and though cycles.

The terms “therapy” and “treatment” as used herein interchangeably,cover any treatment of a disease or disorder, and includes, for example,curing the disease or disorder, preventing the disease or disorder fromoccurring in a subject which may be predisposed to the disease but hasnot yet been diagnosed with the disease or disorder, inhibiting thedisease or disorder, relieving the disease or disorder, providing aprophylactic effect, evolving a beneficial immunological effect; andimproving the quality of life of a subject afflicted by a disease ordisorder.

In one or more embodiments of the present invention, a therapeuticproduct is provided that includes an active agent in a therapeuticallyeffective concentration. Active agents are included in each of thecompositions described herein; however, in some instances the solvent,which is part of the composition, provides therapeutic benefit and thus,can be defined as the at least one active agent. Therapeutic productsare intended for topical treatment of human and animal disorders of bodycavities, or any other disorder, that requires topical application of adrug into a body cavity.

The foamable composition of the present invention can be an emulsion, ormicroemulsion, including an aqueous phase and an organic carrier phase.The organic carrier is selected from a hydrophobic organic carrier (alsotermed herein “hydrophobic solvent”), an emollient, a polar solvent, anda mixture thereof.

A “hydrophobic organic carrier” as used herein refers to a materialhaving solubility in distilled water at ambient temperature of less thanabout 1 gm per 100 mL, more preferable less than about 0.5 gm per 100mL, and most preferably less than about 0.1 gm per 100 mL. It is liquidat ambient temperature. The identification of a hydrophobic organiccarrier or “hydrophobic solvent”, as used herein, is not intended tocharacterize the solubilization capabilities of the solvent for anyspecific active agent or any other component of the foamablecomposition. Rather, such information is provided to aid in theidentification of materials suitable for use as a hydrophobic carrier inthe foamable compositions described herein.

In one or more embodiments, the hydrophobic organic carrier is an oil,such as mineral oil. Mineral oil (Chemical Abstracts Service Registrynumber 8012-95-1) is a mixture of aliphatic, naphthalenic, and aromaticliquid hydrocarbons that derive from petroleum. It is typically liquid;its viscosity is in the range of between about 35 CST and about 100 CST(at 40° C.), and its pour point (the lowest temperature at which an oilcan be handled without excessive amounts of wax crystals forming sopreventing flow) is below 0° C. Term hydrophobic organic carrier doesnot include thick or semi-solid materials, such as white petrolatum,also termed “Vaseline”, which, in certain compositions isdisadvantageous due to its waxy nature and semi-solid texture.

According to one or more embodiments, hydrophobic solvents are liquidoils originating from vegetable, marine or animal sources. Suitableliquid oil includes saturated, unsaturated or polyunsaturated oils. Byway of example, the unsaturated oil may be olive oil, corn oil, soybeanoil, canola oil, cottonseed oil, coconut oil, sesame oil, sunflower oil,borage seed oil, syzigium aromaticum oil, hempseed oil, herring oil,cod-liver oil, salmon oil, flaxseed oil, wheat germ oil, eveningprimrose oils or mixtures thereof, in any proportion.

Suitable hydrophobic solvents also include polyunsaturated oilscontaining poly-unsaturated fatty acids. In one or more embodiments, theunsaturated fatty acids are selected from the group of omega-3 andomega-6 fatty acids. Examples of such polyunsaturated fatty acids arelinoleic and linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoicacid (EPA) and docosahexaenoic acid (DHA). Such unsaturated fatty acidsare known for their skin-conditioning effect, which contribute to thetherapeutic benefit of the present foamable composition. Thus, thehydrophobic solvent can include at least 6% of an oil selected fromomega-3 oil, omega-6 oil, and mixtures thereof. In the context of thepresent invention, oils that possess therapeutically-beneficialproperties are termed “therapeutically active oil”.

Another class of hydrophobic solvents is the essential oils, which arealso considered therapeutically active oil, which contain activebiologically occurring molecules and, upon topical application, exert atherapeutic effect, which is conceivably synergistic to the beneficialeffect of the steroid in the composition.

Another class of therapeutically active oils includes liquid hydrophobicplant-derived oils, which are known to possess therapeutic benefits whenapplied topically.

Silicone oils also may be used and are desirable due to their known skinprotective and occlusive properties. Suitable silicone oils includenon-volatile silicones, such as polyalkyl siloxanes, polyaryl siloxanes,polyalkylaryl siloxanes and polyether siloxane copolymers,polydimethylsiloxanes (dimethicones) andpoly(dimethylsiloxane)-(diphenyl-siloxane) copolymers. These are chosenfrom cyclic or linear polydimethylsiloxanes containing from about 3 toabout 9, preferably from about 4 to about 5, silicon atoms. Volatilesilicones such as cyclomethicones can also be used. Silicone oils arealso considered therapeutically active oil, due to their barrierretaining and protective properties.

In one or more embodiments, the hydrophobic carrier includes at least 2%by weight silicone oil or at least 5% by weight.

The solvent may be a mixture of two or more of the above hydrophobicsolvents in any proportion.

A further class of solvents includes “emollients” that have a softeningor soothing effect, especially when applied to body areas, such as theskin and mucosal surfaces. Emollients are not necessarily hydrophobic.Examples of suitable emollients include hexyleneglycol, propyleneglycol, isostearic acid derivatives, isopropyl palmitate, isopropylisostearate, diisopropyl adipate, diisopropyl dimerate, maleated soybeanoil, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopherylacetate, acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone,glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidylpropionate, myristyl lactate, decyl oleate, propylene glycolricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate,neopentylglycol dicaprylate/dicaprate, isononyl isononanoate,isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyldodecanol, sucrose esters of fatty acids, octyl hydroxystearate andmixtures thereof.

According to one or more embodiments of the present invention, thehydrophobic organic carrier includes a mixture of a hydrophobic solventand an emollient. According to one or more embodiments, the foamablecomposition is a mixture of mineral oil and an emollient in a ratiobetween 2:8 and 8:2 on a weight basis.

A “polar solvent” is an organic solvent, typically soluble in both waterand oil. Examples of polar solvents include polyols, such as glycerol(glycerin), propylene glycol, hexylene glycol, diethylene glycol,propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes,terpen-ols, limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol,other glycols, sulfoxides, such as dimethylsulfoxide (DMSO),dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide,monooleate of ethoxylated glycerides (with 8 to 10 ethylene oxideunits), azone (1-dodecylazacycloheptan-2-one),2-(n-nonyl)-1,3-dioxolane, esters, such as isopropylmyristate/palmitate, ethyl acetate, butyl acetate, methyl proprionate,capric/caprylic triglycerides, octylmyristate, dodecyl-myristate;myristyl alcohol, lauryl alcohol, lauric acid, lauryl lactate ketones;amides, such as acetamide oleates such as triolein; various alkanoicacids such as caprylic acid; lactam compounds, such as azone; alkanols,such as dialkylamino acetates, and admixtures thereof.

According to one or more embodiments, the polar solvent is apolyethylene glycol (PEG) or PEG derivative that is liquid at ambienttemperature, including PEG200 (MW (molecular weight) about 190-210 kD),PEG300 (MW about 285-315 kD), PEG400 (MW about 380-420 kD), PEG600 (MWabout 570-630 kD) and higher MW PEGs such as PEG 4000, PEG 6000 and PEG10000 and mixtures thereof.

In one or more embodiments, the solvent is a mixture (emulsion) of ahydrophobic organic carrier and glycerin, as described, for example, inU.S. Pat. No. 6,544,530. The ratio of hydrophobic organic carrier toglycerin can range from about 1:4 to about 4:1, and more preferably fromabout 1:2 to about 2:1.

In certain cases, a given solvent can be defined as both emollient andpolar solvent.

Certain hydrophobic organic carriers, emollients and polar solventspossess high solubilization capacity for pharmaceutical active agents,and are identified herein as “potent solvents”. A potent solvent as thatterm is used herein, is one that solubilizes a specific active agentsubstantially better than mineral oil or petrolatum, preferably 5 foldbetter than mineral oil or petrolatum, and even 10-fold better thanmineral oil or petrolatum, and even 100-fold better than mineral oil orpetrolatum.

Thus, in one or more embodiments, a foam composition includes at leastone active agent in a therapeutically effective concentration and apotent solvent. In one or more embodiments, the composition includes atleast one active agent in a therapeutically effective concentration andat least one potent solvent in a sufficient amount to substantiallysolubilize the active agent in the composition. In the context of thepresent invention the term “substantially soluble” means that at least95% of the active agent has been solubilized, i.e., less than about 5%is present in the composition in a solid state. In one or moreembodiments, the potent solvent is more than about 40% or more thanabout 60% by weight of the total solvent of the composition.

Examples of active agent/potent solvent combinations include, in anon-limiting manner:

-   -   Betamethasone valerate: Practically insoluble in mineral oil        (<0.01%); soluble more than 1% (w/w) in Glycofurol.    -   Hydrocortisone butyrate: Practically insoluble in mineral oil        (<0.01%); soluble more than 1% in Glycofurol.    -   Metronidazole: Practically insoluble in mineral oil (<0.01%);        soluble more than 1% in dimethyl isosorbide.    -   Ketoconazole: Practically insoluble in mineral oil (<0.01%);        soluble more than 1% in glycofurol, propylene glycol and        dimethyl isosorbide.    -   Mupirocin: Practically insoluble in mineral oil (<0.01%);        soluble more than 1% in glycofurol, hexylene glycol, dimethyl        isosorbide, propylene glycol and polyethylene glycol 400 (PEG        400).    -   Meloxicam, a nonsteroidal anti-inflammatory agent: Practically        insoluble in mineral oil (<0.001%); soluble in propylene glycol:        0.3 mg/mL and in PEG 400: 3.7 mg/mL.    -   Progesterone: Practically insoluble in mineral oil (<0.001%);        soluble in PEG 400: 15.3 mg/mL.

A non-limiting exemplary list of solvents that can be considered aspotent solvents includes polyethylene glycol, propylene glycol, hexyleneglycol, butanediols and isomers thereof, glycerol, benzyl alcohol, DMSO,ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, isosorbide derivatives,such as dimethyl isosorbide, glycofurol and ethoxydiglycol (transcutol).

The present invention also provides a method of designing a foamablecomposition by selecting at least one active agent, selecting a solventthat solubilizes the active agent substantially better than mineral oilor petrolatum, and adjusting the type and concentration of surfactantand gelling agent to provide a foamable composition. This isparticularly useful in fomulating foams incorporating poorly solubleactive agents.

The use of a potent solvent in a foam composition provides an improvedway to deliver poorly soluble active agents to a target area. It isknown that low drug solubility results in poor bioavailability, leadingto decreased effectiveness of treatment. Foam compositions according toone or more embodiments of the present invention for which the solventis a potent solvent are unique because the majority of the active agentis in solution, rather than in particulate form, resulting in highdelivery and improved therapy.

Potent solvents are typically in liquid form. Liquid drug formulationsare generally disadvantageous, since their usage causes unwanteddripping, resulting in inconvenience and inadequate dosing.Unexpectedly, the foams of the present invention are drip-free andthereby provide a superior vehicle for such drugs and enable convenientusage and accurate effective dosing.

Surface-active agents (surfactants) include any agent linking oil andwater in the composition in the form of emulsion. A surfactant'shydrophilic/lipophilic balance (HLB) describes the emulsifier's affinitytoward water or oil. The HLB scale ranges from 1 (totally lipophilic) to20 (totally hydrophilic), with 10 representing an equal balance of bothcharacteristics. Lipophilic emulsifiers form water-in-oil (w/o)emulsions, whereas hydrophilic surfactants form oil-in-water (o/w)emulsions. The HLB of a blend of two emulsifiers equals the weightfraction of emulsifier A times its HLB value plus the weight fraction ofemulsifier B times its HLB value (weighted average).

Any surface-active agent or combinations thereof may be used assurface-active agent. According to one or more embodiments of thepresent invention, the surface-active agent has a hydrophilic lipophilicbalance (HLB) between about 9 and about 14, which is the required HLB(the HLB required to stabilize an O/w emulsion of a given oil) of mostoils and hydrophobic organic carriers. Thus, in one or more embodiments,the composition is a single surface active agent having an HLB valuebetween about 9 and 14, and in one or more embodiments, the compositionis more than one surface active agent and the weighted average of theirHLB values is between about 9 and about 14.

According to one or more embodiments, the surface-active agent in anoleaginous composition (hydrophobic organic carriers of 70% or greater)has a surface-active agent with an HLB in the range of about 3 to about9.

The surface-active agent is selected from anionic, cationic, nonionic,zwitterionic, amphoteric and ampholytic surfactants, as well as mixturesof these surfactants. Such surfactants are well known to those skilledin the therapeutic and cosmetic formulation art. Nonlimiting examples ofpossible surfactants include polysorbates, such as polyoxyethylene (20)sorbitan monostearate (Tween 60) and poly(oxyethylene) (20) sorbitanmonooleate (Tween 80); poly(oxyethylene) (POE) fatty acid esters, suchas Myrj 45, Myrj 49, Myrj 52 and Myrj 59; poly(oxyethylene) alkylylethers, such as poly(oxyethylene) cetyl ether, poly(oxyethylene)palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycolcetyl ether, brij 38, brij 52, brij 56 and brij W1; sucrose esters,partial esters of sorbitol and its anhydrides, such as sorbitanmonolaurate and sorbitan monolaurate; mono or diglycerides,isoceteth-20, sodium methyl cocoyl taurate, sodium methyl oleoyltaurate, sodium lauryl sulfate, triethanolamine lauryl sulfate andbetaines.

In one or more embodiments of the present invention, the surface-activeagent includes at least a non-ionic surfactant. Ionic surfactants areknown to be irritants. Therefore, non-ionic surfactants are preferred inapplications including sensitive tissue such as found in most mucosaltissues, especially when they are infected or inflamed. We havesurprisingly found that non-ionic surfactants alone provide foams ofexcellent quality, i.e. a score of “E” according to the grading scalediscussed herein below.

In one or more embodiments, the surface active agent includes a mixtureof at least one non-ionic surfactant and at least one ionic surfactantin a ratio in the range of about 100:1 to 6:1. In one or moreembodiments, the non-ionic to ionic surfactant ratio is greater thanabout 6:1, or greater than about 8:1; or greater than about 14:1, orgreater than about 16:1, or greater than about 20:1.

In one or more embodiments of the present invention, a combination of anon-ionic surfactant and an ionic surfactant (such as sodium laurylsulphate and cocamidopropylbetaiine) is employed, at a ratio of between1:1 and 20:1, or at a ratio of 4:1 to 10:1. The resultant foam has a lowspecific gravity, e.g., less than 0.1 g/ml.

In one or more embodiments of the present invention, the surface-activeagent includes mono-, di- and tri-esters of sucrose with food fattyacids (sucrose esters), prepared from sucrose and esters of fatty acidsor by extraction from sucro-glycerides. Suitable sucrose esters includethose having high monoester content, which have higher HLB values.

Unlike prior art foamable compositions, the total surface active agentrequired to obtain a foam that is stable, of low specific gravity andhas a fine bubble structure is low. This is desirable because lowersurface active agent levels, particularly of ionic surfactants, reduceskin irritations. Total surface active agent is in the range of about0.1 to about 5% of the foamable composition, and is typically less thanabout 2%, preferably less than about 1%.

It has been unexpectedly found that it is possible to prepare stablefoams with stabilizing surfactants even in very low concentration ofless than about 1% which enable low irritating and low itching vaginalfoams. “Stable foam” denotes shelf life stability of the emulsion andalso a sustainable foam that does not break upon extrusion of thepackage to enable delivery, spreading and expansion of the foamthroughout the entire vaginal cavity before collapse.

The foamable composition includes a polymeric agent to increase theduration/residence time of the composition in the body cavity. Thepolymeric agent serves to stabilize the foam composition and to controldrug duration in the target organ.

Exemplary polymeric agents, which provide means of controlling durationare classified below in a non-limiting manner. In certain cases, a givenpolymer can belong to more than one of the classes provided below.

Bioadhesion has been defined as the attachment of synthetic orbiological macromolecules to a biological tissue. The term mucoadhesionrefers to the special case of bioadhesion where the biological tissue isan epithelium covered by mucous, for example such as found in thevagina, gastrointestinal tract and the nasal cavity. Mucoadhesive agentsare a class of polymeric biomaterials that exhibit the basiccharacteristic of a hydrogel, i.e. swell by absorbing water andinteracting by means of adhesion with the mucous that covers epithelia.

Compositions of the present invention may contain a mucoadhesivemacromolecule or polymer in an amount sufficient to confer bioadhesiveproperties. The bioadhesive macromolecule enhances the delivery ofbiologically active agents on or through the target surface. Themucoadhesive macromolecule may be selected from acidic syntheticpolymers, preferably having at least one acidic group per four repeatingor monomeric subunit moieties, such as poly(acrylic)- and/orpoly(methacrylic) acid (e.g., Carbopol®, Carbomer®), poly(methylvinylether/maleic anhydride) copolymer, and their mixtures and copolymers;acidic synthetically modified natural polymers, such ascarboxymethylcellulose (CMC); neutral synthetically modified naturalpolymers, such as (hydroxypropyl)methylcellulose; basic amine-bearingpolymers such as chitosan; acidic polymers obtainable from naturalsources, such as alginic acid, hyaluronic acid, pectin, gum tragacanth,and karaya gum; and neutral synthetic polymers, such as polyvinylalcohol or their mixtures. An additional group of mucoadhesive polymersincludes natural and chemically modified cyclodextrin, especiallyhydroxypropyl-β-cyclodextrin (HPβCD). Such polymers may be present asfree acids, bases, or salts, usually in a final concentration of about0.01% to about 0.5% by weight.

A suitable bioadhesive macromolecule is the family of acrylic acidpolymers and copolymers, (e.g., Carbopol®). These polymers contain thegeneral structure —[CH₂—CH(COOH)—]_(n). Hyaluronic acid and otherbiologically-derived polymers may be used.

Exemplary bioadhesive or mucoadhesive macromolecules have a molecularweight of at least 50 kDa, or at least 300 kDa, or at least 1,000 kDa.Favored polymeric ionizable macromolecules have not less than 2 molepercent acidic groups (e.g., COOH, SO₃H) or basic groups (NH₂, NRH,NR₂), relative to the number of monomeric units. The acidic or basicgroups can constitute at least 5 mole percent, or at least 10 molepercent, or at least 25, at least 50 more percent, or even up to 100mole percent relative to the number of monomeric units of themacromolecule.

Yet, another group of mucoadhesive agent includes inorganic gellingagents such as silicon dioxide (fumed silica), including but not limitedto, AEROSIL 200 (DEGUSSA).

Many mucoadhesive agents are known in the art to also possess gellingproperties.

A gelling agent controls the residence of a therapeutic composition inthe target site of treatment by increasing the viscosity of thecomposition, thereby limiting the rate of its clearance from the site.Many gelling agents are known in the art to possess mucoadhesiveproperties.

The gelling agent can be a natural gelling agent, a synthetic gellingagent and an inorganic gelling agent. Exemplary gelling agents that canbe used in accordance with one or more embodiments of the presentinvention include, for example, naturally-occurring polymeric materials,such as locust bean gum, sodium alginate, sodium caseinate, egg albumin,gelatin agar, carrageenin gum, sodium alginate, xanthan gum, quince seedextract, tragacanth gum, guar gum, starch, chemically modified starchesand the like, semi-synthetic polymeric materials such as celluloseethers (e.g. hydroxyethyl cellulose, methyl cellulose, carboxymethylcellulose, hydroxy propylmethyl cellulose), guar gum, hydroxypropyl guargum, soluble starch, cationic celluloses, cationic guars, and the like,and synthetic polymeric materials, such as carboxyvinyl polymers,polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers,polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinylchloride polymers, polyvinylidene chloride polymers and the like.Mixtures of the above compounds are contemplated.

Further exemplary gelling agents include the acrylic acid/ethyl acrylatecopolymers and the carboxyvinyl polymers sold, for example, by the B.F.Goodrich Company under the trademark of Carbopol® resins. These resinsconsist essentially of a colloidal water-soluble polyalkenyl polyethercrosslinked polymer of acrylic acid crosslinked with from 0.75% to 2% ofa crosslinking agent such as polyallyl sucrose or polyallylpentaerythritol. Examples include Carbopol® 934, Carbopol® 940,Carbopol® 950, Carbopol® 980, Carbopol® 951 and Carbopol® 981. Carbopol®934 is a water-soluble polymer of acrylic acid crosslinked with about 1%of a polyallyl ether of sucrose having an average of about 5.8 allylgroups for each sucrose molecule.

Yet, another group of gelling agents includes inorganic gelling agents,such as silicone dioxide (fumed silica).

According to one or more embodiments, the foam composition contains atleast one film forming component. The film forming component may includeat least one water-insoluble alkyl cellulose or hydroxyalkyl cellulose.Exemplary alkyl cellulose or hydroxyalkyl cellulose polymers includeethyl cellulose, propyl cellulose, butyl cellulose, cellulose acetate,hydroxypropyl cellulose, hydroxybutyl cellulose, and ethylhydroxyethylcellulose, alone or in combination. In addition, a plasticizer or across linking agent may be used to modify the polymer's characteristics.For example, esters such as dibutyl or diethyl phthalate, amides such asdiethyldiphenyl urea, vegetable oils, fatty acids and alcohols such asoleic and myristyl acid may be used in combination with the cellulosederivative.

In one or more embodiments, the composition of the present inventionincludes a phase change polymer, which alters the composition behaviorfrom fluid-like prior to administration to solid-like upon contact withthe target mucosal surface. Such phase change results from externalstimuli, such as changes in temperature or pH and exposure to specificions (e.g., Ca++).

Non-limiting examples of phase change polymers includepoly(N-isopropylamide), Poloxamer 407® and Smart-Gel® (Poloxamer+PAA).

The polymeric agent is present in an amount in the range of about 0.01%to about 5.0% by weight of the foam composition. In one or moreembodiments, it is typically less than about 1 wt % of the foamablecomposition.

A foam adjuvant is optionally included in the foamable compositions ofthe present invention to increase the foaming capacity of surfactantsand/or to stabilize the foam. In one or more embodiments of the presentinvention, the foam adjuvant agent includes fatty alcohols having 15 ormore carbons in their carbon chain, such as cetyl alcohol and stearylalcohol (or mixtures thereof). Other examples of fatty alcohols arearachidyl alcohol (C20), behenyl alcohol (C22), 1-triacontanol (C30), aswell as alcohols with longer carbon chains (up to C50). Fatty alcohols,derived from beeswax and including a mixture of alcohols, a majority ofwhich has at least 20 carbon atoms in their carbon chain, are especiallywell suited as foam adjuvant agents. The amount of the fatty alcoholrequired to support the foam system is inversely related to the lengthof its carbon chains.

In one or more embodiments of the present invention, the foam adjuvantagent includes fatty acids having 16 or more carbons in their carbonchain, such as hexadecanoic acid (C16) stearic acid (C18), arachidicacid (C20), behenic acid (C22), octacosanoic acid (C28), as well asfatty acids with longer carbon chains (up to C50), or mixtures thereof.As for fatty alcohols, the amount of fatty acids required to support thefoam system is inversely related to the length of its carbon chain.

Optionally, the carbon atom chain of the fatty alcohol or the fatty acidmay have at least one double bond. A further class of foam adjuvantagent includes a branched fatty alcohol or fatty acid. The carbon chainof the fatty acid or fatty alcohol also can be substituted with ahydroxyl group, such as 12-hydroxy stearic acid.

The foam adjuvant according to one or more embodiments of the presentinvention includes a mixture of fatty alcohols, fatty acids and hydroxyfatty acids and derivatives thereof in any proportion, providing thatthe total amount is 0.1% to 5% (w/w) of the carrier mass. Morepreferably, the total amount is 0.4%-2.5% (w/w) of the carrier mass.

While fatty alcohols and fatty acids serve to stabilize the resultantfoam composition, they often provide additional therapeutic properties.Long chain saturated and mono unsaturated fatty alcohols, e.g., stearylalcohol, erycyl alcohol, arachidyl alcohol and docosanol have beenreported to possess antiviral, anti infective, anti-proliferative andanti-inflammatory properties (U.S. Pat. No. 4,874,794). Longer chainfatty alcohols, e.g., tetracosanol, hexacosanol, heptacosanol,octacosanol, triacontanol, etc. are also known for their metabolismmodifying properties and tissue energizing properties. Long chain fattyacids have also been reported to possess anti-infective characteristics.Thus, the therapeutic or cosmetic carrier, containing the foam adjuvantagent of the present invention provides an extra therapeutic benefit incomparison with currently used vehicles, which are inert and non-active.

Lower alcohols having up to 5 carbon atoms in their carbon chainskeleton, such as ethanol, propanol, isopropanol, butanol, iso-butanol,t-butanol and pentanol, are considered less desirable solvents or polarsolvents due to their skin-irritating effect. Thus, the composition issubstantially alcohol-free and should comprise less than about 5% finalconcentration of lower alcohols, preferably less than about 2%, morepreferably less than about 1%.

The therapeutic foam of the present invention may further optionallyinclude a variety of formulation excipients, which are added in order tofine-tune the consistency of the formulation, protect the formulationcomponents from degradation and oxidation and modify their consistency.Such excipients may be selected, for example, from stabilizing agents,antioxidants, humectants, preservatives, colorant and odorant agents andother formulation components, used in the art of formulation.

Aerosol propellants are used to generate and administer the foamablecomposition as a foam. The total composition including propellant,foamable compositions and optional ingredients is referred to as thefoamable carrier. The propellant makes up about 3% to about 25 wt % ofthe foamable carrier. Examples of suitable propellants include volatilehydrocarbons such as butane, propane, isobutane or mixtures thereof, andfluorocarbon gases.

Composition and Foam Physical Characteristics

The compositions described herein, including water, additional solvents,formulation excipients, active agents and propellant creates a stableemulsion that does not exhibit full phase separation at ambienttemperature for at least a year.

Yet, another property of a composition is its level of flow, since acomposition that is not free flowing cannot flow through the dip-tube ofthe aerosol container and create acceptable foam. It has been noted thatin the context of the composition of the present invention, compositionsincluding semi-solid hydrophobic organic carriers, e.g., whitepetrolatum, are excessively viscous and demonstrate poor flowability.

The combination of at least one surface active agent, at least onepolymeric agent and optionally at least one foaming adjuvant, accordingto one or more embodiments of the invention provides a low specificgravity foam having superior expandability, flow properties and sheerbreakability (among other attributes). According to one or moreembodiments of the present invention, the total amount of at least onesurface active agent, at least one polymeric agent and optionally atleast one foaming adjuvant, in combination does not exceed 8% (w/w) offoamable composition. In one or more embodiments, the combined amountsof at least one surface active agent, at least one polymeric agent andoptionally at least one foaming adjuvant is less than 5% (w/w) of foamcomposition. The low solid content improves the flow properties of thefoam, reduces unpleasant skin residue and reduces the cost ofmanufacture. As is demonstrated herein, the foam stability andexpandability are excellent, despite the low levels of these componentsin the foam.

Expandability is an important feature of a product that is intended totreat internal cavities of the body. Thus, in one or more embodiments ofthe present invention, the specific gravity of the foam, upon dischargefrom the foam dispenser is between about 0.02 gr/mL and 0.4 gr/mL, orbetween about 0.04 gr/mL and about 0.14 gr/mL.

The following scale for foam quality is used to evaluate foams.

-   -   E (excellent): very rich and creamy in appearance, does not show        any bubble structure or shows a very fine (small) bubble        structure.    -   G (good): rich and creamy in appearance, very small bubble size,        “dulls” more rapidly than an excellent foam.    -   FG (fairly good): a moderate amount of creaminess noticeable,        bubble structure is noticeable.    -   F (fair): very little creaminess noticeable, larger bubble        structure than a “fairly good” foam.    -   P (poor): no creaminess noticeable, large bubble structure.    -   VP (very poor): dry foam, large very dull bubbles, difficult to        spread on the skin.

Foams that are adequate for topical administration according to thepresent invention have to be of quality grade E or G, upon release fromthe foam dispenser. Smaller bubbles mean more stable foam, which doesnot collapse spontaneously immediately upon discharge from thecontainer. The finer foam structure looks and feels smoother, thusincreasing its usability and appeal.

In one or more embodiments, the foam compositions are stable for aprolonged period of time. Thus, the foam composition does not undergophase separation following at least two freeze and thaw cycles.

Upon discharge from a foam dispenser, e.g., an aerosol can, onto amucosal membrane at about 37° C., the foam expands to reach itsdesignated volume and stays stable as a foam for at least 60 seconds, or2 minutes, or even 3 minutes, following application.

Metered Dosing

In order to provide proper therapy, precise dosing is desired. Accordingto one or more embodiments, the foam therapeutic product is adapted forstorage in a foam dispenser having a metered dose valve for dispensingan accurate dose of drug in the form of a foam. The metered dose valveis selected to release a foam in a volume that is in the size of thetarget body cavity to allow effective spreading of the active agentthroughout the body cavity with substantially minimal overflow.

In one or more embodiments, the meter dose valve provides a unit dose ofbetween about 10 μL and about 1000 μL. Assuming a representative foamdensity (specific gravity) of 0.06 g/mL, a 10 μL valve provides a volumeof about 0.17 mL of foam, and a 1000 μL metered dose valve providesabout 17 mL of foam. Thus, by selecting a specific metered dosing valveand adjusting the foam density by fine tuning formulation parameters andadjusting the ration between the liquid components of the compositionand the propellant, one can design an adequate dosage form according tothe specific target organ cavity

Administration

One limitation of existing vaginal and rectal dosage form relates to thedimensions of the product applicator. In order to administer 5 mL of gel(which is required to attain effective coverage of the vaginal surface),an insert applicator, 10 cm long and about 1.5 cm thick is employed. Itis to be understood that such a thick applicator is found repulsive bypatients, which leads to poor patient compliance. Furthermore, thelength of the applicator, which is beyond the natural depth of a relaxedvaginal cavity, makes it difficult for the patient to accuratelyadminister the composition into the target organ.

By contrast, application of a foam composition according to the presentinvention is not limited by applicator dimensions. The insert is thinand thus, it is acceptable to the patient. The thickness of the aerosolinsert can range between about 0.2 cm and about 1 cm. Likewise, theaerosol insert can be designed in any length, to fit the dimensions ofthe target organ. Thus, the length of a vaginal insert can range betweenabout 2 cm and about 10 cm; the length of an insert for the nasal systemor ear canal can be shorter and the insert for rectal administration canbe adjusted according to the location of the disorder, between about 1cm and about 20 cm. In one or more embodiments, the insert is designedto be flexible, to allow insertion into a body cavity that is difficultto access using a non-flexible insert.

Fields of Application

By including an appropriate active agent in the foamable composition, itis useful in the therapy and prevention of a variety of disorders of abody cavity or mucosal surfaces, including, but not limited to thecranial cavity, the thoracic cavity, the abdominal cavity, the ventralcavity, the vagina, the rectum and penile cavities, the urinary tract,bladder, the cavity between the uterus and the fallopian tubes, theovaries, the nasal cavity, the mouth, the eye, the ear the peritoneum,the large and small bowel, the caecum, bladder, and stomach, and otherbody cavities or spaces, which may accept topically-applied products.

Exemplary treatable disorders are listed below.

Bacterial, Fungal and Viral Infections

Bacterial, fungal and viral infections: a variety of anti-infective,anti-bacterial, anti-fungal and anti-viral agents can be included in thefoam of the present invention, to be used for the treatment and/orprevention of diseases, such as chlamydia, gonorrhea, hepatitis B,herpes, HIV/AIDS, human papallomavirus (HPV) & genital warts; syphilis;bacterial vaginosis, candidiasis, chancroid, granuloma inguinale,lymphogranloma venereum, mucopurulent cervicitis (MPC), molluscumcontagiosum, nongonococcal urethritis (NGU), trichomoniasis, and vulvardisorders.

A variety of active agents, known in the art, can be included in thefoam to be used for the treatment and/or prevention of diseases such asvulvodynia (vulvar pain), yeast infections, genital warts (condyloma)vulvar dystrophy, vulvar intraepithelial neoplasia (VIN), invasivecancer of the vulva, contact dermatitis, pelvic inflammation, pelvicinflammatory disease (PID), genital cancer and cancer of the cervix,vulva or vagina.

Vaginal Dryness

Vaginal dryness is caused by a number of conditions and can be either anoccasional hassle or a chronic problem. A variety of anti-inflammatoryactive agents, hormones, moisturizing, refatting and lubricating agentsand local anesthetic agents can be included in the foam of the presentinvention, to be used for the treatment and/or prevention of vaginaldryness.

Dyspareunia

Dysareunia is pain in the vagina or pelvis experienced during sexualintercourse. A variety of anti-inflammatory active agents, hormones,moisturizing, refatting and lubricating agents and local anestheticagents can be included in the foam of the present invention, to be usedfor the treatment and/or prevention of vaginal pain. Anal and rectaldisease, such as anal abscess/fistula, anal cancer, anal fissure, analwarts, Crohn's disease, hemorrhoids, anal itch, also called pruritusani, fecal incontinence, and polyps of the colon and rectum all may betreated using the foamable composition according to one or moreembodiments of the invention.

The foam composition of the present invention, comprising an activeagent that is known to treat one of said anorectal disorders andadministered rectally, expands effectively in the rectal cavity andprovides optimal coverage of the cavity surface, for improvedtherapeutic results.

HIV and STD Treatment and Prevention

When comprising appropriate protective agents, the foam is activeagainst HIV infection and other infections (bacterial and fungal),including sexually transmitted disease (STD) by creating a protectivelayer and/or decreasing the frequency of transmission. Non-bindingexamples of protective agents include:

Negatively charged sulfated polymers, which have been reported to haveanti-HIV-1 activity and are being considered for development as topicalmicrobicides.

Dextrin sulphate, a microbicide, which in various laboratory andpre-clinical studies, has been shown to block the transfer of HIV virusinto mammalian cells while at the same time not causing injury to normalcell tissue.

Cellulose acetate phthalate, which inactivates HIV-1, herpesvirus types1 (HSV-1) and 2 (HSV-2) and the major nonviral STD pathogens; and foundeffective in animal models for vaginal infection by HSV-2 and simianimmunodeficiency virus.

Several polymers, such as hydroxypropyl methylcellulose phthalate,carrageenans, naphthalene sulfonate polymer, sodium alginate, andcationic polymer, such as chitosan, are insoluble in water and can besolubilized in water by adjusting the pH of the environment to about 6or above, or by the use of appropriate organic solvents. Vaginalsecretions from healthy, reproductive-age women are characteristicallyacidic (pH values of 3.4 to 6.0). Consequently, the topical applicationof a formulation in which such polymers would be soluble (i.e., pH>6)would be expected to contribute to a vaginal environment which isphysiologically undesirable.

Thus, in one embodiment of present invention, there is an advantage toan oily foamable carrier, comprising solvents that solubilizewater-insoluble polymers such as mentioned above. By way of non-limitingexample, such solvents include polyethylene glycol, propylene glycol,hexylene glycol, benzyl alcohol, DMSO, isosorbide derivatives, such asdimethyl isosorbide, glycofurol and ethoxydiglycol (transcutol).

In one or more embodiments of the present invention, the foamcomposition is useful in the therapy of disorders that respond totransmucosal delivery of an active agent. By way of example, suchdisorders include, which respond to hormone therapy, such as hormonereplacement therapy, and other systemic disorders, known to be affectedby drugs that are delivered transmucosally.

The goal of a mucosal vaccine is to induce antigen-specific immuneresponses (cellular and humoral) that are detectable at the mucosalsurfaces of the host. Because many pathogens initiate infection at themucosal surfaces, pathogen-specific mucosal immune responses may providesuperior protection against infectious diseases than immune responsesinduced by parenteral vaccines because parenteral vaccines do not inducemucosal immunity.

In the context of the present invention, the term immunization orvaccination refers to administering a preparation that contains aninfectious agent or its components, which is able to stimulate an immuneresponse that will protect a person from illness due to that agent. Suchvaccines are expected be capable of preventing the transmission orlimiting the severity of sexually-transmitted infections, such as HIVand other infectious disease. Vaccines are usually administered inconjunction with an adjuvant—a substance that is used in a vaccine toimprove the immune response so that less vaccine is needed to produce anon-specific stimulator of the immune response. There are several typesof adjuvants, including, for example, minerals such as aluminumhydroxide, aluminum phosphate and calcium phosphate, oil emulsions,products from bacteria (their synthetic derivatives as well asliposomes) or gram-negative bacteria, endotoxins, cholesterol, fattyacids, aliphatic amines, paraffinic and vegetable oils.

The foam composition of the present invention, comprising an immunizingagent, and optionally an adjuvant and administered onto the mucosaltissue of a body cavity, expands effectively in said cavity and providesoptimal coverage of the cavity surface, for improved therapeuticresults.

Post-Surgical Adhesions Treatment and Prevention

Adhesions are scars that form abnormal connections between tissuesurfaces. Post-surgical adhesion formation is a natural consequence ofsurgery, resulting when tissue repairs itself following incision,cauterization, suturing, or other means of trauma. When comprisingappropriate protective agents, the foam is suitable for the treatment orprevention of post surgical adhesions. The use of foam is particularlyadvantageous because foam can expand in the body cavity and penetrateinto hidden areas that cannot be reached by any other alternative meansof administration.

Hormonal Therapy

The foamable composition of the present invention is suitable foradministering a hormone to a mucosal membrane or a body cavity, in orderto deliver the hormone into the tissue of the target organ, in anydisorder that responds to treatment with a hormone. Topically appliedhormones can also be useful in contraception, when administered in foam,using a metered dose unit.

Active Agents

The composition of the present invention comprises at least one activeagent, also referred to as “drug(s)”. The at least one active agent mayconsist of a single drug or a combination of drugs that can be dissolvedin the water phase or the hydrophobic phase of the carrier composition.Examples of such drugs are antibiotic, antibacterial, antifungal,antiviral, antiinflammatory, anesthetic, analgesic, antiallergic,corticosteroid and antiproliferative medications and mixtures thereof atany proportion. The concentration of drugs may be adopted to exert atherapeutic effect on a disease when applied to an afflicted area.

One important class of drugs comprises antibacterial agents. It is wellknown that bacterial infections are involved in a variety of superficialdisorders of mucosal membranes and body cavities.

In one or more embodiments, the antibiotic agent is selected from theclasses consisting of beta-lactam antibiotics, aminoglycosides,ansa-type antibiotics, anthraquinones, azoles, glycopeptides,macrolides, nucleosides, antibiotic peptides, antibiotic polyenes,antibiotic polyethers, quinolones, antibiotic steroids, sulfonamides,tetracycline, antibiotic metals, including silver, copper, zinc,mercury, tin, lead, bismuth, cadmium, chromium and ions and complexesthereof, oxidizing agents and substances that release free radicalsand/or active oxygen, cationic antimicrobial agents, quaternary ammoniumcompounds, biguanides, triguamides, bisbiguanides and analogs andpolymers thereof and naturally occurring antibiotic compounds.

An antibacterial drug can be active against gram positive andgram-negative bacteria, protozoa, aerobic bacteria and anaerobicbacteria.

By way of example, the antibacterial drugs are selected fromchloramphenicol, beta-lactam antibiotics, aminoglycosides, ansa-typeantibiotics, anthraquinones, azoles, glycopeptides, macrolides,nucleosides, antibiotic peptides, antibiotic polyenes, antibioticpolyethers, quinolones, antibiotic steroids, sulfonamides, tetracycline,antibiotic metals, including silver, copper, zinc, mercury, tin, lead,bismuth, cadmium, chromium and ions and complexes thereof, oxidizingagents and substances that release free radicals and/or active oxygen,cationic antimicrobial agents, quaternary ammonium compounds,biguanides, triguamides, bisbiguanides and analogs and polymers thereofand naturally occurring antibiotic compounds, metronidazlole and itsderivatives and analogs, dicarboxylic acids, such as azelaic acid,slicylates, cyclosporines and any combination thereof at atherapeutically effective concentration.

Another group of antibacterial agents which have broad spectrum activitycomprises strong oxidants and free radical liberating compounds, such asoxygen, hydrogen peroxide, benzoyl peroxide, elemental halogen species,as well as oxygenated halogen species, bleaching agents (e.g., sodium,calcium or magnesium hypochloride and the like), perchlorite species,iodine, iodate, and benzoyl peroxide. Organic oxidizing agents are alsoincluded in the definition of “oxidizing agent” according to the presentinvention, such as quinones. Such agents possess a potent broad spectrumactivity

Antibacterial compositions according to the present invention areselected to treat infections of an afflicted organ. The composition ofthe present invention, comprising a hydrophobic component, wouldfacilitate an enhanced rate of penetration. Furthermore, the intrinsicantibacterial and antiinflammatory effects of the foam adjuvant agents,i.e., fatty alcohols and acids, provides a combined effect for bettertherapeutic response to treatment.

Fungal infections are another object of treatment using the compositionof the present invention. Fungal infection of the vaginal cavity is oneof the most common disorders seen in gynecological practice. Candidiasisis an infection caused by the yeast like fungus Candida albicans oroccasionally other species of candida. Clinical syndromes of candidiasisinclude: (a) oral candidiasis (oral thrush); (b) candidiasis of the skinand genital mucous membrane; and (c) candida paronychia, which inflictsthe nail.

The therapeutic composition may comprise an antifungal drug, which isactive against dermatophytes and candida, selected from the group of,but not limited to azoles, diazoles, triazoles, miconazole, fluconazole,ketoconazole, clotrimazole, itraconazole griseofulvin, ciclopirox,amorolfine, terbinafine, Amphotericin B, potassium iodide, flucytosine(5FC) and any combination thereof at a therapeutically effectiveconcentration. According to one preferred embodiment the active agent ismetronidazole.

The composition of the present invention is particularly beneficial inthe case of viral infections including herpes simplex Type 1 virus.Mollusca are small viral growths that appear singly or in groups on theface, trunk, lower abdomen, pelvis, inner thighs, or penis. Warts are acommon, benign skin tumor caused by viral infection. HPV (HumanPapillomavirus) is a common genital disease.

Viral infections are currently treated with various antiviral agents, assummarized in the following table: Drug Viruses Chemical Type VidarabineHerpesviruses Nucleoside analogue Acyclovir Herpes simplex (HSV)Nucleoside analogue Gancyclovir Cytomegalovirus Nucleoside (CMV)analogue Nucleoside-analog reverse Retroviruses (HIV) Nucleosidetranscriptase inhibitors analogue (NRTI): AZT (Zidovudine), ddl(Didanosine), ddC (Zalcitabine), d4T (Stavudine), 3TC (Lamivudine)Non-nucleoside reverse Retroviruses (HIV) Nucleoside transcriptaseinhibitors analogue (NNRTI): Nevirapine, Delavirdine ProteaseInhibitors: Saquinavir, HIV Peptide Ritonavir, Indinavir, Nelfinaviranalogue Ribavirin Broad spectrum: HCV, Triazole HSV, measles,carboxamide mumps, Lassa fever Amantadine/Rimantadine Influenza Astrains Tricyclic amine Interferons Hepatitis B and C Protein

Any of the above antiviral agents, in a therapeutically effectiveconcentration, can be incorporated in the foam composition of thepresent invention. The composition of the present invention, whichcomprises a hydrophobic organic carrier, would facilitate an enhancedrate of penetration and better topical distribution of any of the abovelisted antiviral drugs. Furthermore, the intrinsic antiviral effects ofthe foam adjuvant agents, i.e., fatty alcohols and acids, provides acombined effect that should result in a better therapeutic response totreatment.

In one or more embodiments, the active agent is a steroid, selected fromthe following groups.

-   -   i. a compound containing a cyclopenta[a]phenanthrene skeleton;    -   ii. a compound, containing a cyclopenta[a]phenanthrene skeleton        carrying one or more functional groups selected from halogens,        alkyl groups, aryl groups, benzyl groups, carboxy groups and        alkoxy groups;    -   iii.    -   iv. a steroid compound, selected from the families of (a)        cardanolides, (b) bufanolides, (c) spirostans, (d)        furostans, (e) steroid alkaloids, (f) a steroid lactone, (g) an        oxo-steroid, (h) a steroid-alcohol and (i) a steroid-amine;    -   v. a steroid compound, where one or more of the        cyclopenta[a]phenanthrene rings is contracted by loss of an        unsubstituted methylene group;    -   vi. a steroid compound, where one or more of the        cyclopenta[a]phenanthrene rings is expandeded by inclusion of a        methylene group;    -   vii. a compound, containing a cyclopenta[a]phenanthrene skeleton        and a carbocyclic or heterocyclic ring component fused to it;    -   viii. an anti-inflammatory steroid;    -   ix. a steroid possessing immunomodulating and/or        anti-inflammatory properties;    -   x. a steroid, selected from the group of low-potency        anti-inflammatory steroids, medium potency anti-inflammatory        steroids and high potency anti-inflammatory steroids;    -   xi. an anti-inflammatory steroid, selected from the group        consisting of hydrocortisone, hydrocortisone acetate, desonide,        betamethasone valerate, clobetasone-17-butyrate, flucinonide,        fluocinolone acetonide, alcometasone dipropionate, mometasone        furoate, prednicarbate, triamcinolone acetonide,        betamethasone-17-benzoate, methylprednisolone aceponate,        betamethasone dipropionate, halcinonide, triamcinolone        acetonide, halobetasol, clobetasol-17-propionate;    -   xii. a steroid hormone;    -   xiii. a steroid hormone, selected from the group consisting of        an androgen, an estrogen and a progestogen    -   xiv. an androgen, selected from the group consisting of        testosterone, testosterone cipionate, testosterone decanoate,        testosterone enantate, testosterone isocaproate, testosterone        phenylpropionate, testosterone propionate, testosterone        undecylate, 5α-dihydrotestosterone, dehydroepiandrosterone (also        termed prasterone and DHEA), androstenedione, androstanediol,        androsterone, androstenolone, prasterone enantate, prasterone        sodium sulfate, ormeloxifene, mesterolone, fluoxymesterone,        methyltestosterone, gestrinone, delmadinone, delmadinone        acetate, chlormadinone, chlormadinone acetate, danazol and        testolactone;    -   xv. an estrogen selected from the group consisting of estradiol,        estradiol benzoate, estradiol cipionate, estradiol dipropionate,        estradiol enantate, estradiol hexahydrobenzoate, estradiol        phenylpropionate, estradiol valerate, polyestradiol phosphate,        estriol, estriol sodium succinate, estriol succinate,        polyestriol phosphate, quinestradol, ethinylestradiol,        estrapronicate, mestranol, estrapronicate and equilin;    -   xvi. a progestogen, selected from the group consisting of        progesterone, norethisterone, norethisterone acetate,        norethisterone enantate, medroxyprogesterone acetate,        delmadinone acetate, flugestone acetate, dydrogesterone,        desogestrel, norgestrel, levonorgestrel, dydrogesterone,        gestodene, chlormadinone acetate, dienogest, drospirenone,        lynestrenol, tybolone, cyproterone acetate, megestrol acetate,        nomegestrol acetate;    -   xvii. an inhibitor of a steroid hormone;    -   xviii. an inhibitor of a steroid hormone, selected from the        group consisting of inhibitors are finasteride, dutasteride and        spironolactone;    -   xix. a vitamin D;    -   xx. a vitamin D, selected from the group consisting of        cholecalciferol, 25-hydroxycholecalciferol,        1α,25-dihydroxycholecalciferol, ergocalciferol,        1α,25-dihydroxyergocalciferol, 22,23-dihydroergocalciferol,        1,24,25-trihydroxycholecalciferol, previtamin D₃, tachysterol₃        (also termed tacalciol), Isovitamin D₃, dihydrotachysterol₃,        (1S)-hydroxycalciol, (24R)-hydroxycalcidiol, 25-fluorocalciol,        ercalcidiol, ertacalciol, (5E)-lsocalciol,        22,23-Dihydroercalciol, (24S)-methylcalciol,        (5E)-(10S)-10,19-Dihydroercalciol, (24S)-Ethylcalciol and        (22E)-R)-Ethyl-22,23-didehydrocalciol; and    -   xxi. a phytosteroid or a phytosterol.

According to another embodiment according to the present invention theat least one active agent is an antiinflammatory or antiallergic agent.An antiinflammatory or antiallergic agent can be selected from the groupof corticosteroids (as listed above), non-steroidal antiinflammatorydrugs (NSAIDs), anti-histamines, immunosuppressants and any combinationthereof at a therapeutically effective concentration.

Since corticosteroid drugs are typically hydrophobic, the carrier of thepresent invention, comprising a hydrophobic organic carrier, is mostsuitable as a vehicle to facilitate better topical distribution and anenhanced rate of penetration of any of the above listed drugs.Furthermore, the intrinsic antiviral, antibacterial and antiinflammatoryeffects of the foam adjuvant agents, i.e., fatty alcohols and acids,provides a combined effect that should result in a better therapeuticresponse to treatment.

Antihistaminic agents may comprise, among other options,diphenhydramine, doxepin, phrilamine maleate, chlorpheniramine,tripelennamine, phenothiazines, promethazine hydrochloride anddimethindene maleate. These drugs, as well as additional antihistaminescan also be incorporated in the composition of the present invention.

A second class of anti-inflammatory agents, which is useful in the foamof the present invention, includes the nonsteroidal anti-inflammatoryagents (NSAIDs). The variety of compounds encompassed by this group iswell-known to those skilled in the art. Specific non-steroidalanti-inflammatory agents useful in the composition invention include,but are not limited to: oxicams, such as piroxicam, isoxicam, tenoxicam,sudoxicam; salicylates, such as salicylic acid, ethyl salicylate, methylsalycilate, aspirin, disalcid, benorylate, trilisate, safapryn, solprin,diflunisal, and fendosal; acetic acid derivatives, such as diclofenac,fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac,tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac,oxepinac, felbinac, and ketorolac; fenamates, such as mefenamic,meclofenamic, flufenamic, niflumic, and tolfenamic acids; propionic acidderivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen,ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen,oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen,and tiaprofenic; and pyrazoles, such as phenylbutazone, oxyphenbutazone,feprazone, azapropazone, and trimethazone.

Any further steroidal and nonsteroidal compounds, having the capacity toprevent, alleviate the symptoms of, treat or cure inflammationprocesses, are generally included, as possible anti-inflammatory agents,according to the present invention.

The therapeutic foam composition of the present invention may alsocomprise an antiinflammatory or antiallergic agent, wherein said agentreduces the occurrence of pro-inflammatory cytokines or inhibits theeffect of pro-inflammatory cytokines.

Mixtures of such anti-inflammatory agents may also be employed, as wellas the dermatologically acceptable salts, esters, amides, prodrugs andderivatives of these agents.

The compositions of the present invention may contain a safe andeffective amount of a topical anesthetic. Examples of local anestheticdrugs include benzocaine, lidocaine, bupivacaine, chlorprocaine,dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine,procaine, cocaine, ketamine, pramoxine, phenol, and therapeuticallyacceptable salts thereof. Mixtures of such anesthetic agents may besynergistically beneficial.

Anti cancer agents can also be used according to the present inventionas the drug of choice for treating for example vaginal, cervical andrectal malignancies. In certain cases, topical cytotoxic andantiproliferative drugs are used to treat or prevent such cancers,including 5-fluorouracil, also called 5-FU. 5-FU, as well as any otheranti-cancer agents, know in the art of cancer medicine, can beincorporated in the foam at therapeutically effective levels.

A preferred family of anticancer drugs, suitable for usage in the foamof the present formulation comprises antiestrogens, such as tamoxifen.Tamoxifen blocks the effects of the hormone estrogen in the body.

A safe and effective amount of an anti-oxidant/radical scavenger may beadded to the compositions of the present invention, preferably fromabout 0.1% to about 10% (w/w), more preferably from about 1% to about 5%(w/w), of the composition.

Anti-oxidants/radical scavengers such as ascorbic acid (vitamin C) andits salts, ascorbyl esters of fatty acids, ascorbic acid derivatives(e.g., magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbylsorbate), tocopherol (vitamin E), tocopherol sorbate, tocopherolacetate, other esters of tocopherol, butylated hydroxy benzoic acids andtheir salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid(commercially available under the tradename Trolox®, gallic acid and itsalkyl esters, especially propyl gallate, uric acid and its salts andalkyl esters, sorbic acid and its salts, lipoic acid, amines (e.g.,N,N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g.,glutathione), dihydroxy fumaric acid and its salts, lycine pidolate,arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, curcumin,lysine, methionine, proline, superoxide dismutase, silymarin, teaextracts, grape skin/seed extracts, melanin, and rosemary extracts maybe used.

The foam of the present invention is suitable for delivering cell andtissue protecting and revitalizing anti-oxidants/radical scavengers.Polyunsaturated fatty acids, containing omega-3 and omega-6 fatty acids(e.g., linoleic and linolenic acid, gamma-linoleic acid (GLA),eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) arebeneficial in the treatment of inflammation conditions. Likewise,emollients and silicone oils exert moisture-retaining and protectiveeffects on the target tissue. Thus, in a preferred embodiment, a tissueprotective foam is provided, wherein the hydrophobic organic carriercomprises in full or in part, a solvent, selected from the group ofemollients, silicone oil and oils, rich in unsaturated fatty acids,thus, affording a synergistic therapeutic effect of theanti-oxidants/radical scavenger agent and the vehicle components.

Active agents, which are known in the art of pharmacology to treatmucosal irritations and inhibit inflammation, can be beneficiallyincorporated in the foam of the present invention.

Examples of such active agents include chamomile extract (matricariarecutitia), cucumber distillate (cucumis sativus), lavender water(lavendula angustifolia), rose water (rosa damascena), witch hazel(hamamelis virginiana), allantoin, bisabolol, rosehip oil, calendulaoil, azulaene, menthol and camphor.

There are several potential uses of the foam, particularly thesilicone-oil based foam, as a lubricating foam. Typical examples aremoisture protection foam and antifriction foam. For such purposes, thefoam can be used in its basic composition (without additionalformulation aids and active ingredients), or with the addition of suchadditives.

According to one embodiment, the at least one active agent is selectedfrom the group of solvent, surface active agent, foam adjuvant andpolymeric agent.

Penetration Enhancers

A penetration enhancer or permeation enhancer is an agent used toincrease the permeability of tissue to a pharmacologically active agentto increase the rate at which the drug diffuses through the skin andenters the tissues and bloodstream. A chemical penetration enhancerincreases skin permeability by reversibly altering the physiochemicalnature of the tissue to reduce its diffusional resistance. According toone or more embodiments of the present invention a penetration enhanceris incorporated into the foam composition.

Examples of penetration enhancers, according to the present inventioninclude: polyols, such as propylene glycol, hexylene glycol, diethyleneglycol, propylene glycol n-alkanols, terpenes, di-terpenes,tri-terpenes, terpen-ols, limonene, terpene-ol, 1-menthol, dioxolane,ethylene glycol, other glycols, and glycerol; sulfoxides, such asdimethylsulfoxide (DMSO), dimethylformamide, methyl dodecyl sulfoxide,dimethylacetamide; monooleate of ethoxylated glycerides (with 8 to 10ethylene oxide units); Azone (1-dodecylazacycloheptan-2-one),2-(n-nonyl)-1,3-dioxolane; esters, such as isopropylmyristate/palmitate, ethyl acetate, butyl acetate, methyl proprionate,capric/caprylic triglycerides, octylmyristate, dodecyl-myristate;myristyl alcohol, lauryl alcohol, lauric acid, lauryl lactate ketones;amides, such as acetamide oleates such as triolein; various surfactants,such as sodium lauryl sulfate; various alkanoic acids such as caprylicacid; lactam compounds, such as azone; alkanols, such as oleyl alcohol;dialkylamino acetates, and admixtures thereof.

Lower alcohols, such as ethanol, propanol, isopropanol, butanol,iso-butanol, t-butanol and pentanol are less desirable penetrationenhancers according to the present invention, due to their irritationproperties.

Yet, another preferred class of penetration enhancers in thecyclodextrines and related compounds. Cyclodextrins are structurallyrelated cyclic oligomaltoses which form a new group of therapeuticexcipients.

The invention is described with reference to the following examples.This invention is not limited to these examples and experiments. Manyvariations will suggest themselves and are within the full intendedscope of the appended claims.

Example 1 General Procedure for Preparing Foam Composition

Aqueous Phase: At least one polymeric agent and at least onesurface-active agent are dissolved in water, with agitation. Thesolution is warmed to about 50° C. to about 70° C. Water solubletherapeutic active ingredients and optional water soluble ingredientsare added with agitation to the Aqueous Phase mixture.

Oil Phase: At least one hydrophobic organic carrier is heated to sameabove temperature. Foam adjuvant agent is added to preheated hydrophobicorganic carrier. Oil soluble therapeutic active agent or agents andoptional oil soluble formulation ingredients are added with agitation tothe Hydrophobic Phase mixture.

The warm Hydrophobic Phase is gradually poured into the warm AqueousPhase, with agitation, followed by Ultraturax or Silversonhomogenization. The mixture is allowed to cool down to ambienttemperature. In case of heat sensitive active ingredients, the activeingredient is added with agitation to the mixture after cooling toambient temperature. The mixture, at ambient temperature, is added to anaerosol container, the container is sealed and appropriate amount ofpropellant (about 3% to about 25 w % of the composition mass) is addedunder pressure into the container.

Example 2 Emulsion Foam Carrier Composition for Vaginal and RectalTreatment

The ingredients listed in the table below are combined to form afoamable emulsion composition. Version Version Version VersionIngredient No. 1 No. 2 No. 3 No. 4 Hydrophobic MCT oil 30 — 15 12organic carrier IPM — 30 — 12 Foam adjuvant Stearyl Alcohol 1.0 1.0 1.01.0 Surface-active GMS 1.0 1.0 1.0 1.0 agent PEG S-40 3 3 3 3Polysorbate-60 1 1 1 1 Polymeric agent Xanthan Gum 0.3 0.3 — — MethocelELV15 0.4 0.4 — — Natrosol — — 1.5 1.5 Other Ingredients Antioxidant 0.20.2 0.2 0.2 Preservatives 1.0 1.0 1.0 1.0 Propellant* Propane/butane 8.08.0 8.0 8.0 Water Water To 100 To 100 To 100 To 100 Foam Specific ND NDND 0.06 gravity (gr/mL)

The liquefied or gas propellant can be added at a concentration of about3% to about 25%. The compositions use only non-ionic surface activeagents, and the total amount of surface active agent, foam adjuvants andpolymeric agent ranged from 1.4 to 2.1% (w/w). The foam of this exampleis useful as a carrier of active agents, as exemplified in examplesbelow. It is also useful as lubricating foam, for various purposes.

Example 3 Further Mixed Oil Foam Carrier Composition for Vaginal andRectal Treatment

The ingredients listed in the table below are combined to form afoamable emulsion composition. Version Version No. 1 ˜25% No. 2 ˜12.5%Ingredient Oil Oil Hydrophobic Mineral oil 10.2 5.6 organic Isopropyl5.0 2.5 carrier myristate MCT oil 7.0 3.8 Foam adjuvant Stearyl Alcohol2.0 2.0 agent Surface-active Brij 72 2.5 2.5 agent Brij 721 1.0 1.0Cocoa amido 0.5 0.5 propyl betaine Polymeric Xanthan Gum 0.3 — agentNatrosol — 0.3 Methocel ELV15 0.5 — Propellant* Propane/butane 6.0 6.0Water Water To 100 To 100

The liquefied or gas propellant can be added at a concentration of about3% to about 25%. The foams of this example have a non-ionic surfaceactive agent to ionic surface active agent ratio (w/w) of 20:1 and 14:1for versions 1 and 2, respectively. Total amounts of surface activeagent foam adjuvant and polymeric agent is in the range of about 1.75 toabout 3.5% (w/w).

The compositions are useful as carriers of active therapeutic activeingredients, as exemplified in examples below. It is also useful aslubricating foam, for various purposes.

The following examples, representing optional drug-containing foams, areprototype formulations, which have not been optimized for stability andinter-component compatibility. Such optimization is a customary need,which can be done, using means, known to those skilled in the art oftherapeutic formulation

Example 4 Antibacterial Foam Composition for Vaginal Vaginosis and OtherVaginal and Rectal Infections

% w/w % w/w % w/w Metronidazole 1.00 — — Clindamycin — 2.00 2.00 Mineraloil 6.00 6.00 6.00 Mineral oil 6.00 6.00 6.00 Isopropyl myristate 6.006.00 6.00 Glyceryl monostearate 1.00 1.00 1.00 Stearyl alcohol 1.00 1.001.00 Xantan gum 0.30 0.30 0.30 Methocel K100M 0.30 0.30 0.30 Tween 601.00 1.00 1.00 MYRJ 52 3.00 3.00 3.00 Cocoamidopropylbetaine 0.50 0.50 —Parabens (phenoxy ethanol and methyl, ethyl 0.80 0.80 0.80 and propylhydroxy benzoate mixture) Propellant 10.00 10.00 10.00 Propane/butane *Water to 100.0 to 100.0 to 100.0

The liquefied or gas propellant can be added at a concentration of about3% to about 25%. The foams of this example have a non-ionic surfaceactive agent to ionic surface active agent ratio ranging from about 20:1to about 6:1. In one version, no ionic surface active agent was present.

Example 5 Antifungal Foam Composition

Version 1 Version 2 Version 3 Version 4 Ingredient “Miconazole”“Clotrimazole” “Econazole” “Nystatin” Carrier % w/w % w/w % w/w % w/wIngredients Mineral oil 30 — — 10 Isopropyl — 30 — 10 myristate MCT oil— — 30 10 Stearyl 2.0 2.0 2.0 2.0 Alcohol Myrj 40 — — 0.8 — GMS 2.0 2.02.0 2.0 Natrosol 1.0 1.0 1.0 1.0 Active Ingredients Miconazole 1 — — —Clotrimazole — 2 — — Econazole — — 1 Nystatin 100,000 Units/grPropellant* 10.0 10.0 10.0 10.0 Propane/ butane Water To 100 To 100 To100 To 100

The liquefied or gas propellant can be added at a concentration of about3% to about 25%. The foams of this example have a non-ionic surfaceactive agent to ionic surface active agent ratio ranging from about 16:1to about 6:1. Total surface active agent, foam adjuvant and polymericagent ranges from 2.05 to 3.5% (w/w). They are useful in the treatmentof fungal and yeast infections.

Example 6 Corticosteroid Foam Composition

% w/w % w/w % w/w % w/w % w/w Mineral oil 5.60 5.60 5.60 5.60 5.60Isopropyl myristate 5.60 5.60 5.60 5.60 5.60 Glyceryl monostearate 0.450.45 1.00 1.00 1.00 Stearyl alcohol 0.85 0.85 0.85 0.85 0.85 Myrj 522.60 2.60 2.60 2.60 2.60 Xantan gum 0.26 — — — — Methocel K100M 0.26 — —— — Chitosan — — 1.00 — — Hyaluronic acid — — — 0.50 0.50 Avicel CL611 —2.00 2.00 2.00 2.00 TWEEN 80 0.90 0.90 0.90 0.90 0.90 Cocoamidopropylbetaine 0.41 0.41 0.41 0.41 0.41 Betametasone valerate 0.12 — 0.12 0.12— Hydrocortisone butyrate — 0.10 — — 0.10 Propylene glycol 3.00 3.003.00 3.00 3.00 Parabens (phenoxy 0.8 0.8 0.8 0.8 0.8 ethanol and methyl,ethyl and propyl hydroxy benzoate mixture) Propellant 12.00 12.00 12.0012.00 12.00 Propane/butane* Water To 100 To 100 To 100 To 100 To 100

The liquefied or gas propellant can be added at a concentration of about3% to about 25%. The foams of this example have a non-ionic surfactantto ionic surfactant ratio ranging from about 20:1 to about 14:1. Totalsurface active agent, foam adjuvant and polymeric agent ranged fromabout 2% to about 3.5% (w/w).

Example 7 Antiviral Foam Composition

Version 1 Version 2 Version 3 Ingredient “Acyclovir” “Acyclovir”“α-Interferon” Carrier Ingredients % w/w % w/w % w/w Mineral oil 48.411.0 5.4 Isopropyl myristate — 5.0 2.5 MCT oil — 7.0 3.5 Stearyl Alcohol0.7 0.4 0.2 Water To 100 To 100 To 100 Sucrose ester SP70 0.8 0.8 0.8Distilled monoglyceride 1.2 0.6 Sodium lauryl sulphate 0.05 0.1 0.1Xanthan Gum 0.2 0.3 0.3 Methocel ELV15 0.2 0.6 0.6 Active IngredientsAcyclovir 5 5 — α-Interferon — — 105 IU/g Propellant* 6.0 6.0 10.0Propane/butane

The liquid is added at a concentration of about 3% to about 25%. Thefoam of this example has a non-ionic surfactant to ionic surfactantration ranging from 20:1 to 14:1. Total surface active agent, foamingadjuvant and polymeric agent ranged from about 2% to about 3.5% (w/w).

Example 8 Compositions Consisting of Corticosteroids, Antifungal andAntiviral Agents

Ingredient % w/w % w/w % w/w % w/w Betamethasone valerate 0.1Ketoconazole 2.0 2.0 Acyclovir 5.0 Caprylic/Capric Triglycerides 60.960.0 59.0 56.0 Propylene glycol 10.0 10.0 5.0 Hexylene glycol 10.0Potent solvent — — — 5.0 Lecithin 10.0 10.0 10.0 10.0 Stearyl alcohol5.0 5.0 5.0 5.0 Glyceryl monostearate 2.0 2.0 2.0 2.0 PVP K90 2.0 2.02.0 2.0 Preservative 0.3 0.3 0.3 0.3 Propellant 10.0 12.0 12.0 10.0Propane/butane * Purified water** TO 100 TO 100 TO 100 TO 100

The liquefied or gas propellant can be added at a concentration of about3% to about 25%. Water content in these compositions was about 10%

Example 9 Comparative Tolerability and Acceptability Study of a PlaceboFoam Composition Vs. a Conventional Gel

Four patients compared the use of the foam preparation of Example 4,Version 2, with a conventional intravaginal gel preparation (MetrogelVaginal, 3M). They were asked to describe their feeling about theapplication of each of the products and to give their general rating foreach of the products on a scale of 0-3 (0=poor; 1=barely acceptable;2=acceptable and 3=excellent).

As demonstrated in the following table, the foam preparation obtainedhigher rates in all aspects of the test. Foam Preparation MetroGelVaginal Property Mean Rating Mean Rating Ease of preparation prior to2.8 0.6 administration Ease of insertion 2. 1.2 Comfort upon insertion2.0 1.2 Ease of dosing 2.0 1.5 Lack of dripping 2.0 1.3 Ease of removal2.2 1.6 Comfort upon removal 1.9 1.3 Overall rating 2.2 1.3

Example 10 Animal Model for Drug Administration and Duration

The composition of Example 4, Version 2 was prepared, with the additionof 0.2% methylene blue as coloring agent. A female sheep wasadministered intra-vaginally one dose of the foam (metered dose, 50 μL).The vagina and cervix were observed by colposcopy and recordedphotographically. The insertion was very easy. Foam expanded effectivelyand vaginal cavity and cervix area were fully covered. Fifteen minutesafter treatment, the vagina was swabbed. Colposcopy revealed that theentire vaginal cavity and cervix area were still covered by the bluepigment. There was no overflow of the foam and no dripping afteradministration. No signs of irritation were observed.

Example 11 Very Low Surfactants Formulation

% w/w % w/w % w/w % w/w Mineral oil 20.00 20.00 30.00 Isopropylpalmitate 15.00 MCT oil 15.00 Glyceryl monostearate 1.00 1.00 Sucroseester and Sorbitan stearate 0.20 0.20 0.20 0.20 (Arlatone 2121) PemulenTR1 00.20 Pemulen TR2 00.20 00.20 Methocel K100 00.30 00.30 00.30 00.30Xantan Gum TWEEN 80 11.00 TEA 00.10 .0.10 00.10 Propellant 112.00 112.00112.00 112.00 Water To 100 To 100 To 100 To 100

The formulations of Example 11 are made stable with unexpectedly lowsurfactant concentration making them highly non irritating and of loweritching potential for conditions of damaged infected or diseasedcondition vaginal mucous.

Although various embodiments that incorporate the teachings of thepresent invention have been shown and in detail herein, those skilled inthe art can readily devise many other varied embodiments thatincorporate these teachings. All references mentioned herein areincorporated by reference.

1. An alcohol-free foamable composition for application to a body cavityor a mucosal surface, comprising: at least one organic carrier selectedfrom a hydrophobic organic carrier, a polar solvent, an emollient andmixtures thereof, at a concentration of about 2% to about 75% by weight;about 0.2% to about 5% by weight at least one surface-active agent;about 0.01% to about 5% weight at least one polymeric agent, selectedfrom a bioadhesive agent, a gelling agent, a film forming agent and aphase change agent; at least one active agent at a therapeuticallyeffective concentration; a liquefied or compressed gas propellant at aconcentration of about 3% to about 25% by weight of the totalcomposition, which upon release from an aerosol container provides anexpanded foam suitable for topical administration.
 2. An oleaginousfoamable composition for administration to a body cavity or mucosalsurface comprising: at least one organic carrier selected from ahydrophobic organic carrier, an emollient, a polar solvent, and mixturesthereof, at a concentration of about 70% to about 99% by weight, atleast one surface active agent at a concentration of about 0.2% to about15%; at least one polymeric agent, selected from a bioadhesive agent, agelling agent, a film forming agent and a phase change agent at aconcentration of about 0.1% to about 5% by weight; at least one activeagent at a therapeutically effective concentration; a liquefied orcompressed gas propellant at a concentration of about 3% to about 25% byweight of the total composition. which upon release from an aerosolcontainer provides a expanded foam suitable for topical administration.3. The foamable composition of claim 1, wherein the concentration of theorganic carrier is selected from (1) about 2% to about 5% by weight ofcomposition; (2) about 5% to about 10% by weight of composition; (3)about 10% to about 20% by weight of composition; and (4) about 20% toabout 75% by weight of composition.
 4. The foamable composition of claim1 or 2, further including about 0.1% to about 5% by weight of atherapeutically active foam adjuvant is selected from the groupconsisting of a fatty alcohol having 15 or more carbons in their carbonchain; a fatty acid having 16 or more carbons in their carbon chain;fatty alcohols, derived from beeswax and including a mixture ofalcohols, a majority of which has at least 20 carbon atoms in theircarbon chain; a fatty alcohol having at least one double bond; a fattyacid having at least one double bond; a branched fatty alcohol; abranched fatty acid; a fatty acid substituted with a hydroxyl group;cetyl alcohol; stearyl alcohol; arachidyl alcohol; behenyl alcohol;1-triacontanol; hexadecanoic acid; stearic acid; arachidic acid; behenicacid; octacosanoic acid; 12-hydroxy stearic acid and mixtures thereof.5. The foamable composition of claim 1 or 2, wherein the organic carriercomprises a mixture of mineral oil and an emollient in a ratio between2:8 and 8:2 on a weight basis.
 6. The foamable composition of claims 1or 2, wherein the surface-active agent is selected from a non ionicsurfactant, a cationic surfactant, an amphoteric surface-active agentand a surface-active agent.
 7. The foamable composition of claim 6,wherein the surface-active agent is a mixture of at least one non ionicsurface-active agent and at least one ionic surface-active agent in aratio selected from (1) between about 20:1 and about 1:1; and (2)between about 100:1 and about 6:1.
 8. The foamable composition of claim6, wherein the surface-active agent is essentially non-ionic.
 9. Thefoamable composition of claim 1 or 2, wherein the surface-active agentis non-ionic surface active agent in a concentration of below 1%. 10.The foamable composition of claim 1, wherein the surface-active agenthas HLB value of more than
 9. 11. The foamable composition of claim 2,wherein the surface-active agent has HLB value of less than
 9. 12. Thefoamable composition of claim 4, wherein the combined amount of foamadjuvant agent surface-active agent and polymeric agent is less thanabout 8% (w/w).
 13. The foamable composition of claim 4, wherein thecombined amount of foam adjuvant agent surface-active agent andpolymeric agent is less than about 5% (w/w).
 14. The foamablecomposition of claim 1 or 2 wherein the active agent is selected for thetreatment of a disease, the etiology of which is bacterial, fungal,viral, parasitic, inflammatory, autoimmune, allergic, hormonal,malignant and combinations thereof.
 15. The therapeutic composition ofclaim 1 or 2 wherein active agent is selected from the group of anorganic carrier, surface active agent, foam adjuvant and polymericagent.
 16. The foamable composition of claim 1 or 2, wherein the activeagent is selected for the treatment of a mucosal disorder, a vaginaldisorder, a vulvar disorder, an anal disorder, the vagina, the rectumand penile cavities, the urinary tract, bladder, the cavity between theuterus and the fallopian tubes, the ovaries, a disorder of therespiratory system, post-surgical adhesion.
 17. The foamable compositionof claim 1 or 2, wherein the active agent is selected for the treatmentof a disorder, selected from the group of inflammation, bacterialInfections, fungal Infections, parasitic infections, viral infections,benign tumors, malignant tumors, pain, itch, allergy, dryness, wound,cut, a tissue adhesion abnormality, a hormonal abnormality, whichrespond to administration of the one active agent.
 18. The foamablecomposition of claim 1 or 2 wherein the disorder is selected frombacterial, fungal and viral infections, chlamydia infection, gonorrheainfection, hepatitis B, herpes, a neoplasm, a benign tumor, HIV/AIDS,human papillomavirus (HPV), genital warts, bacterial vaginosis,candidiasis, chancroid, granuloma Inguinale, lymphogranloma venereum,mucopurulent cervicitis (MPC), molluscum contagiosum, nongonococcalurethritis (NGU), trichomoniasis, vulvar disorders, vulvodynia, vulvarpain, yeast infection, vulvar dystrophy, vulvar intraepithelialneoplasia (VIN), contact dermatitis, pelvic inflammation, endometritis,salpingitis, oophoritis, genital cancer, cancer of the cervix, cancer ofthe vulva, cancer of the vagina, vaginal dryness, dyspareunia, anal andrectal disease, anal abscess/fistula, anal cancer, anal fissure, analwarts, Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecalincontinence, constipation, polyps of the colon and rectum,post-surgical adhesions, disorders that respond to hormone therapy andbirth control.
 19. The composition of claim 1 or 2 wherein the activeagent is selected from the group consisting of antibacterial agents,anti-parasitic agents, antifungal agents, antiviral agents, steroidalanti-inflammatory agents, non-steroidal immunomodulating agents,immunosuppressants, anti-allergic agents, anticancer agents, hormones,androgens, estrogens, progesterones, contraceptive agents, retinoids,vitamin A, vitamin B, vitamin D, local anesthetic agents, lubricatingagents and immunizing agent.
 20. The composition of claim 1 and 2wherein the active agent is selected from negatively charged sulfatedpolymers, hyaluronic acid, dextrin sulphate, cellulose acetatephthalate, hydroxypropyl methylcellulose phthalate, carrageenans,naphthalene sulfonate polymer, sodium alginate, a cationic polymer andchitosan.
 21. The composition of claim 1 or 2 wherein the active agentis intended for trans-mucosal delivery.
 22. The foamable composition ofclaim 21 wherein the active agent is intended for the treatment of asystemic disease, which responds to administration of the active agent.23. The foamable composition of claim 2 wherein the organic carriercontains more than 50% of a potent solvent.
 24. The foamable compositionof claim 23 wherein the potent solvent is selected from polyethyleneglycol, propylene glycol, hexylene glycol, butane-diol and isomersthereof, glycerol, benzyl alcohol, DMSO, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, isosorbide derivatives, such as dimethylisosorbide, glycofurol and ethoxydiglycol (transcutol).
 25. The foamablecomposition of claim 1 or 2, wherein said composition is contained in anaerosol can, equipped with a metered dose valve and an insertapplicator.
 26. The foamable composition of claim 1 or 2, wherein thebody cavity is selected from the group consisting of cranial cavity, thethoracic cavity, the abdominal cavity, the ventral cavity, the vagina,the rectum and penile cavities, the urinary tract, bladder, the cavitybetween the uterus and the fallopian tubes, the ovaries, the nasalcavity, the mouth, the eye, the ear the peritoneum, the large and smallbowel, the caecum, bladder, and stomach, and other body cavities orspaces, which may accept topically-applied products.
 27. A device foradministration of a foamable composition onto a mucosal membrane or intoa body cavity, comprising an aerosol can, a metered dose valve and aninsert applicator.
 28. The device of claim 27, wherein the metered doseis adjusted to afford a dose between about 10 μL and about 1000 μL. 29.The device of claim 28, wherein the metered dose is adjusted to afford adose, selected from (1) between about 50 μL and about 200 μL; and (2)between about 200 μL and about 1000 μL.
 30. The device of claim 27,wherein the metered dose is adjusted to afford a final volume of foambetween about 0.17 mL about 17 mL.
 31. The device of claim 27, whereinthe thickness of said insert applicator is selected from (1) betweenabout 0.2 cm and about 0.4 cm; (2) between about 0.4 cm and about 0.8cm; and between about 0.8 cm and about 1 cm.
 32. The device of claim 27,wherein the length of said insert applicator is between about 1 cm andabout 20 cm.
 33. The device of claim 27, wherein the thickness andlength of said insert applicator are designed to match the dimensions ofthe target body cavity.
 34. A method of treating, alleviating orpreventing a disorder, comprising administering topically to a mucosalsurface or a body cavity a therapeutically effective amount of the foamcomposition of claim 1 or
 2. 35. The method of claim 34, wherein thedisorder is selected from bacterial, fungal and viral infections,chlamydia infection, gonorrhea infection, hepatitis B, herpes, aneoplasm, a benign tumor, HIV/AIDS, human papillomavirus (HPV), genitalwarts, bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale,lymphogranloma venereum, mucopurulent cervicitis (MPC), molluscumcontagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvardisorders, vulvodynia, vulvar pain, yeast infection, vulvar dystrophy,vulvar intraepithelial neoplasia (VIN), contact dermatitis, pelvicinflammation, endometritis, salpingitis, oophoritis, genital cancer,cancer of the cervix, cancer of the vulva, cancer of the vagina, vaginaldryness, dyspareunia, anal and rectal disease, cnal abscess/fistula,anal cancer, anal fissure, anal warts, Crohn's disease, hemorrhoids,anal itch, pruritus ani, fecal incontinence, constipation, polyps of thecolon and rectum, post-surgical adhesions, disorders that respond tohormone therapy and birth control.
 36. The method of claim 34, whereinthe body cavity is selected from the group consisting of cranial cavity,the thoracic cavity, the abdominal cavity, the ventral cavity, thevagina, the rectum and penile cavities, the urinary tract, bladder, thecavity between the uterus and the fallopian tubes, the ovaries, thenasal cavity, the mouth, the eye, the ear the peritoneum, the large andsmall bowel, the caecum, bladder, and stomach, and other body cavitiesor spaces, which may accept topically-applied products.